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1.  Prognostic role of apoptosis-related gene functional variants in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy 
OncoTargets and therapy  2015;8:147-155.
Single-nucleotide polymorphisms in apoptosis-related genes have been shown to play a role in the efficacy of platinum-based chemotherapy and may influence clinical outcomes. Our study aimed to evaluate the correlations of four functional single-nucleotide polymorphisms − FAS −670 A>G, FAS ligand −844 T>C, survivin −31 G>C, and survivin 9386 C>T – with drug response and clinical outcomes in advanced non-small-cell lung cancer patients who received platinum-based chemotherapy.
Materials and methods
Polymorphisms were evaluated using the polymerase chain reaction-based restriction fragment-length polymorphism technique.
Patients with the CC genotype of FAS −670 A>G had worse overall survival (OS) than those with the CT or TT genotype (P=0.044), with median OS values of 20.1 months, 22.8 months, and 26.0 months, respectively. Furthermore, progression-free survival was associated with the FAS −670 A>G polymorphism (P=0.032). In addition, patients with the TC and CC genotypes of survivin 9386 C>T experienced improved survival compared with patients with the TT genotype (median OS 31.4 months and 22.8 months, respectively).
The functional FAS −670 A>G and survivin 9386 C>T polymorphisms are potential independent prognostic factors in advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy.
PMCID: PMC4298310  PMID: 25609982
lung cancer; FAS −670 A>G; survivin 9386 C>T; polymorphism; chemotherapy response
2.  The clinical significance of CDK1 expression in oral squamous cell carcinoma 
Objectives: To evaluate the clinical significance of cyclin-dependent kinase 1 (CDK1) in 77 oral squamous cell carcinomas (OSCC) using immunohistochemical methods. Study Design: Immunohistochemical expression of CDK1 was compared with various clinicopathological features in 77 OSCC and 60 controlled epithelia adjacent to the tumours. In addition, correlation of CDK1 expression and prognostic and the 5-year accumulative survival rate of OSCC were investigated. Results: The CDK1 protein was expressed in 52 cases of 77 tumor tissues (67.5%), compared with 21 cases of 60 controlled (35.0%). The expression of CDK1 was significantly correlated with the histological grade of OSCC (P<0.05). The CDK1 protein was over-expressed in recurrent tumors or in those with lymph node metastasis. Statistical analysis showed a significant reduction in the 5-year accumulative survival rate in CDK1 positive cases compared with CDK1 negative cases (P<0.05). Namely, the CDK1 positive patients had poor prognosis. Conclusions: The expression of CDK1 might serve as malignant degree and prognostic markers for the survival of OSCC.
Key words:Cyclin-dependent kinase 1 (CDK1), oral squamous cell carcinoma (OSCC), immunohistochemistry, cell proliferation.
PMCID: PMC4320424  PMID: 25129248
3.  Protein Kinase Cι maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis 
Molecular cancer research : MCR  2013;11(12):1624-1635.
Protein kinase Cι (PKCι) is an oncogene in lung and ovarian cancers. PKCι is an attractive therapeutic target for treatment of lung cancer, particularly those whose tumors express elevated PKCι. However, it is unknown whether PKCι is a viable therapeutic target in the ovary, and virtually nothing is known about the mechanism by which PKCι drives ovarian tumorigenesis. Here, we demonstrate that PKCι maintains a tumor-initiating cell (TIC) phenotype that drives ovarian tumorigenesis. A highly tumorigenic population of cells from human ovarian cancer cell lines exhibit properties of cancer stem-like TICs including self-renewal, clonal expansion, expression of stem-related genes, enhanced transformed growth in vitro, and aggressive tumor-initiating activity in vivo. Genetic disruption of PKCι inhibits the proliferation, clonal expansion, anchorage-independent growth and enhanced tumorigenic properties of ovarian TICs. Biochemical analysis demonstrates that PKCι acts through its oncogenic partner Ect2 to activate a Mek-Erk signaling axis that drives the ovarian TIC phenotype. Genomic analysis reveals that PRKCI and ECT2 are coordinately amplified and overexpressed in the majority of primary ovarian serous tumors, and these tumors exhibit evidence of an active PKCι-Ect2 signaling axis in vivo. Finally, we demonstrate that auranofin is a potent and selective inhibitor of oncogenic PKCι signaling that inhibits the tumorigenic properties of ovarian TIC cells in vitro and in vivo. Our data demonstrate that PKCι is required for a TIC phenotype in ovarian cancer, and that auranofin is an attractive therapeutic strategy to target deadly ovarian TICs in ovarian cancer patients.
PMCID: PMC3888959  PMID: 24174471
4.  Surgically treated incidentally discovered low-grade gliomas are mostly IDH mutated and 1p19q co-deleted with favorable prognosis 
Objective: LGGs (low-grade gliomas) are sometimes encountered by chance during radiological examinations. These incidentally discovered LGGs (IDLGGs) were relatively under-studied in the literature. The purpose of current study is to review a cohort of patients with IDLGGs surgically treated in our institution for their clinical and histological aspects and determine their IDH1 and 1p19q status. Methods: All patients with hemispheric LGGs receiving operation in our institution between 2001 and 2004 were reviewed. Clinical, radiological and treatment data of the patients were collected and IDLGGs were retrieved and compared with symptomatic LGGs. Histological review was carried out and formalin-fixed paraffin embedded (FFPE) tissues of IDLGGs were examined for IDH1/IDH2 mutation and 1p/19q codeletion. Results: Twenty three IDLGGs (10.4%) were identified while 196 patients had symptomatic LGGs. The reasons for patients with IDLGGs having radiological examination included trauma (47.8%), dizziness (26.1%), unrelated headache (21.7%), and health checkup (4.4%). Clinically, patients with IDLGGs had higher preoperative KPS (P < 0.001), smaller tumor volume (P = 0.014), lower frequency of eloquent areas involvement (P < 0.001) and higher rate of complete resection (P = 0.037) comparing to those with symptomatic LGGs. Histologically, there is a preponderance of oligodendroglial differentiation with 6 oligodendrogliomas and 11 oligoastrocytomas but there were also 6 astrocytomas. IDH1 mutation and 1p/19q co-deletion were detected in 95.7% (22/23) and 69.6% (16/23) of IDLGGs, respectively. The latter encompassed all but one of the cases of oligodendroglial tumors. Patients with IDLGGs had longer overall survival than those with symptomatic LGGs (P = 0.027). Conclusions: We conclude that the majority of IDLGGs are IDH1 mutated and are predominantly oligodendroglial tumors. With a median follow-up of 9.3 years to our series, we conclude that patients with IDLGGs had better prognosis than those with symptomatic LGGs. The favorable prognosis of IDLGGs may be accounted by the higher practicability of extensive resection, non-eloquent tumor location and smaller tumor volume. Frequent IDH1 mutation and 1p/19q co-deletion in IDLGGs may also contribute to the favorable prognosis of this subgroup of patients.
PMCID: PMC4313984
Low-grade glioma; incidental; surgery; pathology; prognosis
5.  Quantitative Dynamic Modelling of the Gene Regulatory Network Controlling Adipogenesis 
PLoS ONE  2014;9(10):e110563.
Gene regulatory networks (GRNs) coherently coordinate the expressions of genes and control the behaviors of cellular systems. The complexity in modeling a quantitative GRN usually results from inaccurate parameter estimation, which is mostly due to small sample sizes. For better modeling of GRNs, we have designed a small-sample iterative optimization algorithm (SSIO) to quantitatively model GRNs with nonlinear regulatory relationships. The algorithm utilizes gene expression data as the primary input and it can be applied in case of small-sized samples. Using SSIO, we have quantitatively constructed the dynamic models for the GRNs controlling human and mouse adipogenesis. Compared with two other commonly-used methods, SSIO shows better performance with relatively lower residual errors, and it generates rational predictions on the adipocyte responses to external signals and steady-states. Sensitivity analysis further indicates the validity of our method. Several differences are observed between the GRNs of human and mouse adipocyte differentiations, suggesting the differences in regulatory efficiencies of the transcription factors between the two species. In addition, we use SSIO to quantitatively determine the strengths of the regulatory interactions as well as to optimize regulatory models. The results indicate that SSIO facilitates better investigation and understanding of gene regulatory processes.
PMCID: PMC4204895  PMID: 25333650
6.  Regulation of Expression of abcA and Its Response to Environmental Conditions 
Journal of Bacteriology  2014;196(8):1532-1539.
The ATP-dependent transporter gene abcA in Staphylococcus aureus confers resistance to hydrophobic β-lactams. In strain ISP794, abcA is regulated by the transcriptional regulators MgrA and NorG and shares a 420-nucleotide intercistronic region with the divergently transcribed pbp4 gene, which encodes the transpeptidase Pbp4. Exposure of exponentially growing cells to iron-limited media, oxidative stress, and acidic pH (5.5) for 0.5 to 2 h had no effect on abcA expression. In contrast, nutrient limitation produced a significant increase in abcA transcripts. We identified three additional regulators (SarA, SarZ, and Rot) that bind to the overlapping promoter region of abcA and pbp4 in strain MW2 and investigated their role in the regulation of abcA expression. Expression of abcA is decreased by 10.0-fold in vivo in a subcutaneous abscess model. In vitro, abcA expression depends on rot and sarZ regulators. Moenomycin A exposure of strain MW2 produced an increase in abcA transcripts. Relative to MW2, the MIC of moenomycin was decreased 8-fold for MW2ΔabcA and increased 10-fold for the MW2 abcA overexpresser, suggesting that moenomycin is a substrate of AbcA.
PMCID: PMC3993360  PMID: 24509312
7.  Egg survival is reduced by grave-soil microbes in the carrion beetle, Nicrophorus vespilloides 
BMC Evolutionary Biology  2014;14(1):208.
Nicrophorus vespilloides eggs are deposited into the soil in close proximity to the decomposing vertebrate carcasses that these insects use as an obligate resource to rear their offspring. Eggs in this environment potentially face significant risks from the bacteria that proliferate in the grave-soil environment following nutrient influx from the decomposing carcass. Our aims in this paper are twofold: first, to examine the fitness effects of grave-soil bacteria to eggs, and second, to quantify egg immunocompetence as a defence against these bacteria.
Our results provide strong evidence that grave-soil microbes significantly reduce the survival of Nicrophorus eggs. Females provided with microbe rich carcasses to rear broods laid fewer eggs that were less likely to hatch than females given uncontaminated carcasses. Furthermore, we show that egg hatch success is significantly reduced by bacterial exposure. Using a split-brood design, which controlled for intrinsic differences in eggs produced by different females, we found that eggs washed free of surface-associated bacteria show increased survival compared to unwashed eggs. By contrast, eggs exposed to the entomopathogen Serratia marcescens show decreased survival compared to unexposed eggs. We next tested the immune competence of eggs under challenge from bacterial infection, and found that eggs lacked endogenous production of antimicrobial peptides, despite well-developed responses in larvae. Finally, we found that despite lacking immunity, N. vespilloides eggs produce an extraembryonic serosa, indicating that the serosa has lost its immune inducing capacity in this species.
The dependency on ephemeral resources might strongly select for fast developing animals. Our results suggest that Nicrophorus carrion beetles, and other species developing on ephemeral resources, face a fundamental trade-off between egg immunity and development time.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-014-0208-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4189599  PMID: 25260512
Trade-off; Burying beetle; Egg immunity; Developmental speed
8.  Molecular characterization of duck enteritis virus CHv strain UL49.5 protein and its colocalization with glycoprotein M 
Journal of Veterinary Science  2014;15(3):389-398.
The UL49.5 gene of most herpesviruses is conserved and encodes glycoprotein N. However, the UL49.5 protein of duck enteritis virus (DEV) (pUL49.5) has not been reported. In the current study, the DEV pUL49.5 gene was first subjected to molecular characterization. To verify the predicted intracellular localization of gene expression, the recombinant plasmid pEGFP-C1/pUL49.5 was constructed and used to transfect duck embryo fibroblasts. Next, the recombinant plasmid pDsRed1-N1/glycoprotein M (gM) was produced and used for co-transfection with the pEGFP-C1/pUL49.5 plasmid to determine whether DEV pUL49.5 and gM (a conserved protein in herpesviruses) colocalize. DEV pUL49.5 was thought to be an envelope glycoprotein with a signal peptide and two transmembrane domains. This protein was also predicted to localize in the cytoplasm and endoplasmic reticulum with a probability of 66.7%. Images taken by a fluorescence microscope at different time points revealed that the DEV pUL49.5 and gM proteins were both expressed in the cytoplasm. Overlap of the two different fluorescence signals appeared 12 h after transfection and continued to persist until the end of the experiment. These data indicate a possible interaction between DEV pUL49.5 and gM.
PMCID: PMC4178140  PMID: 24690604
colocalization; duck enteritis virus; intracellular localization; molecular characterization; UL49.5 protein
9.  Differential Modulation by IL-17A of Cholangitis versus Colitis in IL-2Rα Deleted Mice 
PLoS ONE  2014;9(8):e105351.
IFN-γ is a signature Th1 cell associated cytokine critical for the inflammatory response in autoimmunity with both pro-inflammatory and potentially protective functions. IL-17A is the hallmark of T helper 17 (Th17) cell subsets, produced by γδT, CD8+ T, NK and NKT cells. We have taken advantage of our colony of IL-2Rα−/− mice that spontaneously develop both autoimmune cholangitis and inflammatory bowel disease. In this model CD8+ T cells mediate biliary ductular damage, whereas CD4+ T cells mediate induction of colon-specific autoimmunity. Importantly, IL-2Rα−/− mice have high levels of interferon γ (IFN-γ), and interleukin-17A (IL-17A). We produced unique double deletions of mice that were either IL-17A−/−IL-2Rα−/− or IFN-γ−/−IL-2Rα−/− to specifically address the precise role of these two cytokines in the natural history of autoimmune cholangitis and colitis. Of note, deletion of IL-17A in IL-2Rα−/− mice led to more severe liver inflammation, but ameliorated colitis. In contrast, there were no significant changes in the immunopathology of double knock-out IFN-γ−/− IL-2Rα−/− mice, compared to single knock-out IL-2Rα−/− mice with respect to cholangitis or colitis. Furthermore, there was a significant increase in pathogenetic CD8+ T cells in the liver of IL-17A−/−IL-2Rα−/− mice. Our data suggest that while IL-17A plays a protective role in autoimmune cholangitis, it has a pro-inflammatory role in inflammatory bowel disease. These data take on particular significance in the potential use of anti-IL-17A therapy in humans with primary biliary cirrhosis.
PMCID: PMC4136813  PMID: 25133396
10.  Radiographic analysis of the restoration of hip joint center following open reduction and internal fixation of acetabular fractures: a retrospective cohort study 
Unfavorable reduction is considered one of the key factors leading to joint degeneration and compromised clinical outcome in acetabular fracture patients. Besides the columns, walls, and superior dome, the postoperative position of hip joint center (HJC), which is reported to affect hip biomechanics, should be considered during the assessment of quality of reduction. We aimed to evaluate the radiographic restoration of HJC in acetabular fractures treated with open reduction and internal fixation.
Patients with a displaced acetabular fracture that received open reduction and internal fixation in the authors’ institution during the past five years were identified from the trauma database. The horizontal and vertical shifts of HJC were measured in the standard anteroposterior view radiographs taken postoperatively. The radiographic quality of fracture reduction was graded according to Matta’s criteria. The relationships between the shift of HJC and the other variables were evaluated.
Totally 127 patients with 56 elementary and 71 associated-type acetabular fractures were included, wherein the majority showed a medial (89.0%) and proximal (93.7%) shift of HJC postoperatively. An average of 2.8 mm horizontal and 2.2 mm vertical shift of HJC were observed, which correlated significantly with the quality of fracture reduction (P < 0.001 for both). The horizontal shift of HJC correlated with the fracture type (P = 0.022).
The restoration of HJC correlates with the quality of reduction in acetabular fractures following open reduction and internal fixation. Further studies are required to address the effects of HJC shift on the biomechanical changes and clinical outcomes of hip joint, especially in poorly reduced acetabular fractures.
PMCID: PMC4137070  PMID: 25124773
Acetabular fracture; Open reduction and internal fixation; Hip joint center; Radiography
11.  Increased methylation of the MOR gene proximal promoter in primary sensory neurons plays a crucial role in the decreased analgesic effect of opioids in neuropathic pain 
Molecular Pain  2014;10:51.
The analgesic potency of opioids is reduced in neuropathic pain. However, the molecular mechanism is not well understood.
The present study demonstrated that increased methylation of the Mu opioid receptor (MOR) gene proximal promoter (PP) in dorsal root ganglion (DRG) plays a crucial role in the decreased morphine analgesia. Subcutaneous (s.c.), intrathecal (i.t.) and intraplantar (, not intracerebroventricular (i.c.v.) injection of morphine, the potency of morphine analgesia was significantly reduced in nerve-injured mice compared with control sham-operated mice. After peripheral nerve injury, we observed a decreased expression of MOR protein and mRNA, accompanied by an increased methylation status of MOR gene PP, in DRG. However, peripheral nerve injury could not induce a decreased expression of MOR mRNA in the spinal cord. Treatment with 5-aza-2′-deoxycytidine (5-aza-dC), inhibited the increased methylation of MOR gene PP and prevented the decreased expression of MOR in DRG, thereby improved systemic, spinal and periphery morphine analgesia.
Altogether, our results demonstrate that increased methylation of the MOR gene PP in DRG is required for the decreased morphine analgesia in neuropathic pain.
PMCID: PMC4137045  PMID: 25118039
Neuropathic pain; Epigenetics; Opioids
12.  Community Analysis of Arbuscular Mycorrhizal Fungi in Roots of Poncirus trifoliata and Citrus reticulata Based on SSU rDNA 
The Scientific World Journal  2014;2014:562797.
Morphological observation of arbuscular mycorrhizal fungi (AMF) species in rhizospheric soil could not accurately reflect the actual AMF colonizing status in roots, while molecular identification of indigenous AMF colonizing citrus rootstocks at present was rare in China. In our study, community of AMF colonizing trifoliate orange (Poncirus trifoliata L. Raf.) and red tangerine (Citrus reticulata Blanco) were analyzed based on small subunit of ribosomal DNA genes. Morphological observation showed that arbuscular mycorrhizal (AM) colonization, spore density, and hyphal length did not differ significantly between two rootstocks. Phylogenetic analysis showed that 173 screened AMF sequences clustered in at least 10 discrete groups (GLO1~GLO10), all belonging to the genus of Glomus Sensu Lato. Among them, GLO1 clade (clustering with uncultured Glomus) accounting for 54.43% clones was the most common in trifoliate orange roots, while GLO6 clade (clustering with Glomus intraradices) accounting for 35.00% clones was the most common in red tangerine roots. Although, Shannon-Wiener indices exhibited no notable differences between both rootstocks, relative proportions of observed clades analysis revealed that composition of AMF communities colonizing two rootstocks varied severely. The results indicated that native AMF species in citrus rhizosphere had diverse colonization potential between two different rootstocks in the present orchards.
PMCID: PMC4138779  PMID: 25162057
13.  Chlamydial infection of the gastrointestinal tract: a reservoir for persistent infection 
Pathogens and disease  2013;68(3):88-95.
The mechanism by which chlamydiae persist in vivo remains undefined; however, chlamydiae in most animals persist in the gastrointestinal tract (GI) and are transmitted via the fecal-oral route. Oral infection of mice with Chlamydia muridarum was previously shown to establish a long-term persistent infection in the GI tract. In this study, BALB/c, DBA/2 and C57Bl/6 mice, infected orally with C. muridarum, were infected in the cecum for as long as 100 days in the absence of pathology. The primary target tissue was the cecum although the large intestine was also infected in most animals. A strong serum IgG and cecal IgA antibody response developed. Lymphocyte proliferation assays to chlamydial antigen on mesenteric lymph node cells were positive by day 10 and peaked on days 15–21, but the response returned to baseline levels by 50 days, despite the ongoing presence of the organism in the cecum. Since studies have shown that women and men become infected orally with chlamydiae, we propose that the GI tract is a site of persistent infection and that immune down-regulation in the gut allows chlamydiae to persist indefinitely. As a result, women may become reinfected via contamination of the genital tract from the lower GI tract.
PMCID: PMC3751173  PMID: 23843274
14.  Laforin Prevents Stress-Induced Polyglucosan Body Formation and Lafora Disease Progression in Neurons 
Molecular neurobiology  2013;48(1):49-61.
Glycogen, the largest cytosolic macromolecule, is soluble because of intricate construction generating perfect hydrophilic-surfaced spheres. Little is known about neuronal glycogen function and metabolism, though progress is accruing through the neurodegenerative epilepsy Lafora disease (LD) proteins laforin and malin. Neurons in LD exhibit Lafora bodies (LBs), large accumulations of malconstructed insoluble glycogen (polyglucosans). We demonstrated that the laforin-malin complex reduces LBs and protects neuronal cells against endoplasmic reticulum stress-induced apoptosis. We now show that stress induces polyglucosan formation in normal neurons in culture and in brain. This is mediated by increased glucose-6-phosphate allosterically hyperactivating muscle glycogen synthase (GS1), and is followed by activation of the glycogen digesting enzyme glycogen phosphorylase. In the absence of laforin, stress-induced polyglucosans are undigested and accumulate into massive LBs, and in laforin-deficient mice stress drastically accelerates LB accumulation and LD. The mechanism through which laforin-malin mediates polyglucosan degradation remains unclear but involves GS1 dephosphorylation by laforin. Our work uncovers the presence of rapid polyglucosan metabolism as part of the normal physiology of neuroprotection. We propose that deficiency in the degradative phase of this metabolism, leading to LB accumulation and resultant seizure predisposition and neurodegeneration, underlies LD.
PMCID: PMC3722335  PMID: 23546741
Laforin; muscle glycogen synthase; polyglucosan; ER stress; neuron; Lafora body; Lafora disease; neurodegeneration
15.  MDRL lncRNA Regulates the Processing of miR-484 Primary Transcript by Targeting miR-361 
PLoS Genetics  2014;10(7):e1004467.
Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but whether lncRNAs operate in the processing of miRNA primary transcript is unclear. Also, whether lncRNAs are involved in the regulation of the mitochondrial network remains to be elucidated. Here, we report that a long noncoding RNA, named mitochondrial dynamic related lncRNA (MDRL), affects the processing of miR-484 primary transcript in nucleus and regulates the mitochondrial network by targeting miR-361 and miR-484. The results showed that miR-361 that predominantly located in nucleus can directly bind to primary transcript of miR-484 (pri-miR-484) and prevent its processing by Drosha into pre-miR-484. miR-361 is able to regulate mitochondrial fission and apoptosis by regulating miR-484 levels. In exploring the underlying molecular mechanism by which miR-361 is regulated, we identified MDRL and demonstrated that it could directly bind to miR-361 and downregulate its expression levels, which promotes the processing of pri-miR-484. MDRL inhibits mitochondrial fission and apoptosis by downregulating miR-361, which in turn relieves inhibition of miR-484 processing by miR-361. Our present study reveals a novel regulating model of mitochondrial fission program which is composed of MDRL, miR-361 and miR-484. Our work not only expands the function of the lncRNA pathway in gene regulation but also establishes a new mechanism for controlling miRNA expression.
Author Summary
Long non-coding RNAs (lncRNAs) have been shown to be involved in a wide range of biological functions. However, studies linking individual lncRNA to the mitochondrial fission program remain scarce. Also, it remains unknown whether lncRNAs can operate in the processing of miRNA primary transcript. Here, we provide causal evidence for the involvement of the lncRNA MDRL in the mitochondrial dynamics and the processing of miR-484 primary transcript in cardiomyocyte. We identified MDRL which can act as an endogenous ‘sponge’ that directly binds to miR-361 and downregulates its expression levels. miR-361 can directly bind to primary transcript of miR-484 and prevent its processing by Drosha into pre-miR-484. MDRL inhibits mitochondrial fission and apoptosis by miR-361 and miR-484. Our present study reveals a novel regulating model which is composed of MDRL, miR-361 and miR-484. Modulation of their levels may provide a new approach for tackling myocardial infarction.
PMCID: PMC4109843  PMID: 25057983
16.  Areca Nut Components Affect COX-2, Cyclin B1/cdc25C and Keratin Expression, PGE2 Production in Keratinocyte Is Related to Reactive Oxygen Species, CYP1A1, Src, EGFR and Ras Signaling 
PLoS ONE  2014;9(7):e101959.
Chewing of betel quid (BQ) increases the risk of oral cancer and oral submucous fibrosis (OSF), possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa.
Primary gingival keratinocytes (GK cells) were exposed to areca nut (AN) components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. PGE2/PGF2α production was measured by enzyme-linked immunosorbent assays.
Areca nut extract (ANE) stimulated PGE2/PGF2α production, and upregulated the expression of cyclooxygenase-2 (COX-2), cytochrome P450 1A1 (CYP1A1) and hemeoxygenase-1 (HO-1), but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR), Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by α–naphthoflavone (a CYP 1A1/1A2 inhibitor), PD153035 (EGFR inhibitor), pp2 (Src inhibitor), and manumycin A (a Ras inhibitor). ANE-induced PGE2 production was suppressed by piper betle leaf (PBL) extract and hydroxychavicol (two major BQ components), dicoumarol (a NAD(P)H:Quinone Oxidoreductase - NQO1 inhibitor) and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2αproduction.
CYP4501A1, reactive oxygen species (ROS), EGFR, Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer. Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response.
PMCID: PMC4106785  PMID: 25051199
17.  DNA methyltransferase3a expression is an independent poor prognostic indicator in gastric cancer 
AIM: To explore the alteration of DNA methyltransferase expression in gastric cancer and to assess its prognostic value.
METHODS: From April 2000 to December 2010, 227 men and 73 women with gastric cancer were enrolled in the study. The expression of DNA methyltransferases (DNMTs), including DNMT1, DNMT3a and DNMT3b, in the 300 cases of gastric carcinoma, of which 85 had paired adjacent normal gastric mucus samples, was evaluated by immunohistochemistry using a tissue microarray. Serum anti-Helicobacter pylori (H. pylori) IgG was detected by enzyme-linked immunosorbent assay (ELISA). The relationships between the above results and the clinicopathological characteristics were analyzed. Their prognostic value was evaluated using the Cox proportional hazards model.
RESULTS: In gastric cancer, expression of DNMTs was mainly seen in the nucleus. Weak staining was also observed in the cytoplasm. Expression of DNMT1, DNMT3a and DNMT3b in gastric cancer was significantly higher compared to that in the paired control samples (60.0% vs 37.6%, 61.2% vs 4.7%, and 94.1% vs 71.8%, P < 0.01). The overall survival rate was significantly higher in the DNMT3a negative group than in the DNMT3a positive group in gastric cancer patients (Log-rank test, P = 0.032). No significant correlation was observed between DNMT1 and DNMT3b expression and the overall survival time (Log-rank test, P = 0.289, P = 0.347). Multivariate regression analysis indicated that DNMT3a expression (P = 0.025) and TNM stage (P < 0.001), but not DNMT1 (P = 0.54) or DNMT3b (P = 0.62), were independent prognostic factors in gastric cancer. H. pylori infection did not induce protein expression of DNMTs.
CONCLUSION: The results suggest that expression of DNMT3a is an independent poor prognostic indicator in gastric cancer. DNMT3a might play an important role in gastric carcinogenesis.
PMCID: PMC4081693  PMID: 25009393
DNA methyltransferase; Prognosis; Gastric cancer; Expression; Helicobacter pylori
18.  Effects of lycium barbarum polysaccharides on neuropeptide Y and heat-shock protein 70 expression in rats exposed to heat 
Biomedical Reports  2014;2(5):687-692.
The purpose of the present study was to investigate the effects of high ambient temperature on the neuropeptide Y (NPY) mRNA level in the hypothalamus, the plasma concentration of corticotropin-releasing hormone (CRH), cortisol (Cor), heat-shock protein 70 (HSP70) and epinephrine (EPI), and the intervention of lycium barbarum polysaccharides (LBPs) in rats. Compared to the control (CN) group, the plasma levels of CRH, Cor, HSP70 and EPI were markedly increased, and the level of NPY mRNA was downregulated in the high ambient temperature (HT) group. By contrast, rats in the HT + LBP (HTL) group had: i) a significantly enhanced expression of HSP70 compared to the HT and CN groups; ii) clearly increased plasma levels of CRH, Cor and EPI compared to the CN group; and iii) a markedly upregulated expression of NPY mRNA compared to the HT group. Thus, the results showed that high-temperature environments may damage the body, and LBPs have a potentially protective function by increasing the expression of HSP70 and NPY.
PMCID: PMC4106567  PMID: 25054012
high-temperature environments; heat-shock protein 70; neuropeptide Y; lycium barbarum polysaccharides
19.  CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity 
Acta Neuropathologica  2014;128(2):291-303.
Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1291-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4159569  PMID: 24839957
20.  Estimation of the Exposure of the UK Population to the Bovine Spongiform Encephalopathy Agent through Dietary Intake During the Period 1980 to 1996 
PLoS ONE  2014;9(4):e94020.
Although the incidence of variant Creutzfeldt-Jakob disease (vCJD) has declined to 1 since 2012 in the UK, uncertainty remains regarding possible future cases and the size of the subclinical population that may cause secondary transmission of the disease through blood transfusion. Estimating the number of individuals who were exposed to the bovine spongiform encephalopathy (BSE) infectious agent and may be susceptible to vCJD will help to clarify related public health concerns and plan strategies. In this paper, we explore this estimate by describing the probability of potential exposure due to dietary intake throughout the BSE epidemic period from 1980 to 1996 as a stochastic Poisson process. We estimate the age- and gender-specific exposure intensities in food categories of beef and beef-containing dishes, burgers and kebabs, pies, and sausages, separating the two periods of 1980–1989 and 1990–1996 due to the specified bovine offal legislation of 1989. The estimated total number of (living) exposed individuals during each period is 5,089,027 (95% confidence interval [CI] 4,514,963–6,410,317), which was obtained by multiplying the population size of different birth cohorts by the probability of exposure via dietary intake and the probability of survival until the end of 2013. The estimated number is approximately doubled, assuming a contamination rate of . Among those individuals estimated, 31,855 (95% CI 26,849–42,541) are susceptible to infection. We also examined the threshold hypothesis by fitting an extreme-value distribution to the estimated infectious dose of the exposed individuals and obtained a threshold estimate of 13.7 bID50 (95% CI 6.6–26.2 bID50) (Weibull). The results provide useful information on potential carriers of prion disease who may pose a threat of infection via blood transfusion and thus provide insight into the likelihood of new incidents of vCJD occurring in the future.
PMCID: PMC3988046  PMID: 24736322
21.  Primary testicular lymphoma with subcutaneous masses as the sole manifestation of the first relapse and central nervous system lymphoma as the second relapse: A case report and literature review 
Oncology Letters  2014;7(6):1881-1884.
Primary testicular lymphoma (PTL) accounts for ~1% of all non-Hodgkin’s lymphomas and has a marked tendency for systemic relapse. The current study presents a unique case of testicular diffuse large B-cell lymphoma of non-germinal center B-cell subtype, with subcutaneous masses as the sole manifestation of the first relapse and central nervous system lymphoma as the second relapse. Subcutaneous relapse and subsequent brain relapse are extremely rare signs of PTL dissemination. The patient received methotrexate-based combined chemotherapy and achieved a partial response. This case presents a rare pattern of treatment failure in this malignant clinical entity.
PMCID: PMC4049739  PMID: 24932252
primary testicular lymphoma; subcutaneous soft tissue; relapse
22.  A Nonparametric Shape Prior Constrained Active Contour Model for Segmentation of Coronaries in CTA Images 
We present a nonparametric shape constrained algorithm for segmentation of coronary arteries in computed tomography images within the framework of active contours. An adaptive scale selection scheme, based on the global histogram information of the image data, is employed to determine the appropriate window size for each point on the active contour, which improves the performance of the active contour model in the low contrast local image regions. The possible leakage, which cannot be identified by using intensity features alone, is reduced through the application of the proposed shape constraint, where the shape of circular sampled intensity profile is used to evaluate the likelihood of current segmentation being considered vascular structures. Experiments on both synthetic and clinical datasets have demonstrated the efficiency and robustness of the proposed method. The results on clinical datasets have shown that the proposed approach is capable of extracting more detailed coronary vessels with subvoxel accuracy.
PMCID: PMC3988742  PMID: 24803950
23.  A Novel Chitosan-γPGA Polyelectrolyte Complex Hydrogel Promotes Early New Bone Formation in the Alveolar Socket Following Tooth Extraction 
PLoS ONE  2014;9(3):e92362.
A novel chitosan-γPGA polyelectrolyte complex hydrogel (C-PGA) has been developed and proven to be an effective dressing for wound healing. The purpose of this study was to evaluate if C-PGA could promote new bone formation in the alveolar socket following tooth extraction. An animal model was proposed using radiography and histomorphology simultaneously to analyze the symmetrical sections of Wistar rats. The upper incisors of Wistar rats were extracted and the extraction sockets were randomly treated with gelatin sponge, neat chitosan, C-PGA, or received no treatment. The extraction sockets of selected rats from each group were evaluated at 1, 2, 4, or 6 wk post-extraction. The results of radiography and histopathology indicated that the extraction sockets treated with C-PGA exhibited lamellar bone formation (6.5%) as early as 2 wk after the extraction was performed. Moreover, the degree of new bone formation was significantly higher (P < 0.05) in the extraction sockets treated with C-PGA at 6 wk post-extraction than that in the other study groups. In this study, we demonstrated that the proposed animal model involving symmetrical sections and simultaneous radiography and histomorphology evaluation is feasible. We also conclude that the novel C-PGA has great potential for new bone formation in the alveolar socket following tooth extraction.
PMCID: PMC3962413  PMID: 24658174
24.  MC3 Mucoepidermoid carcinoma cell line enriched cancer stem-like cells following chemotherapy 
Oncology Letters  2014;7(5):1569-1575.
Mucoepidermoid carcinoma (MEC) is common in human salivary glands. Surgery is the preferred treatment method for MEC and chemotherapy is often administered following surgery as an adjuvant cancer treatment; however, chemotherapy does not completely prevent tumor recurrence. Emerging evidence has indicated the existence of cancer stem-like (CSL)-cells in tumors. CSL-cells are important in the development, invasion and drug resistance of carcinomas. The present study aimed to investigate whether chemotherapy enriched the CSL-cells in the MEC cell line of MC3 using 5-fluorouracil (5-Fu). The MC3 cells were treated with 5-Fu, which enhanced the spherogenesis and vitality of the cells and upregulated the pluripotency gene, octamer-binding transcription factor 4. Side population analysis demonstrated that the proportion of CSL-cells also increased. These findings showed that compared with other types of cancer cells, chemotherapy was unable to effectively kill the CSL-cells resulting in an enriched CSL-cell subpopulation with a higher resistance to chemotherapy, which may have been key the recurrence of MEC.
PMCID: PMC3997737  PMID: 24765178
cancer stem-like cells; mucoepidermoid carcinoma; octamer-binding transcription factor 4; cluster of differentiation 44; 5-fluorouracil
25.  Cryogen-free heterodyne-enhanced mid-infrared Faraday rotation spectrometer 
Optics Express  2013;21(1):740-755.
A new detection method for Faraday rotation spectra of paramagnetic molecular species is presented. Near shot-noise limited performance in the mid-infrared is demonstrated using a heterodyne enhanced Faraday rotation spectroscopy (H-FRS) system without any cryogenic cooling. Theoretical analysis is performed to estimate the ultimate sensitivity to polarization rotation for both heterodyne and conventional FRS. Sensing of nitric oxide (NO) has been performed with an H-FRS system based on thermoelectrically cooled 5.24 μm quantum cascade laser (QCL) and a mercury-cadmium-telluride photodetector. The QCL relative intensity noise that dominates at low frequencies is largely avoided by performing the heterodyne detection in radio frequency range. H-FRS exhibits a total noise level of only 3.7 times the fundamental shot noise. The achieved sensitivity to polarization rotation of 1.8 × 10−8 rad/Hz1/2 is only 5.6 times higher than the ultimate theoretical sensitivity limit estimated for this system. The path- and bandwidth-normalized NO detection limit of 3.1 ppbv-m/Hz1/2 was achieved using the R(17/2) transition of NO at 1906.73 cm−1.
PMCID: PMC3635467  PMID: 23388967
(300.6390) Spectroscopy, molecular; (300.6310) Spectroscopy, heterodyne; (140.5965) Semiconductor lasers, quantum cascade

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